Adaptable tissue-specific endothelial cells for organ regeneration

用于器官再生的适应性组织特异性内皮细胞

• 批准号: 10594461
• 负责人: Shahin Rafii
• 金额: $ 101.78万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594461
• 关键词: Adult; Allogenic; Award; Blood; Blood Vessels; Cardiac; Cell Line; Cells; Cicatrix; Clinic; Clinical Trials; Coculture Techniques; Code; Endothelial Cells; Engineering; FDA approved; Fibrosis; Functional disorder; Genetic Transcription; Goals; Growth Factor; Heart; Hematopoietic; Hepatic; Heterogeneity; Homeostasis; Human; In Vitro; Infusion procedures; Intention; Lung; Macaca nemestrina; Mission; Molecular; Monkeys; Morphogenesis; Mus; National Heart, Lung, and Blood Institute; Natural regeneration; Organ; Organoids; Outcome; Pathway interactions; Production; RNA; Recovery; Regenerative Medicine; Research; Safety; Signal Transduction; Specific qualifier value; Technology; Testing; Therapeutic; Tissue Engineering; Tissue Transplantation; Tissues; Translating; Translations; Transplantation; cellular transduction; efficacious treatment; experimental study; fetal; follow-up; healing; in vivo; induced pluripotent stem cell; innovation; knock-down; lung repair; nonhuman primate; novel; organ injury; organ regeneration; organ repair; overexpression; programs; reconstitution; regenerative; repaired; replacement tissue; stem cells; tissue repair; tumorigenesis; vascular contributions

PROJECT ABSTRACT The overarching goal of our proposed research program is to develop a discovery pipeline that will enable identification of transcriptional codes for engineering tissue-specific endothelial cells (ECs) for therapeutic organ regeneration of heart, lung and blood. Therapies for organ regeneration promises unlimited access to the replacement tissues. However, despite breakthroughs in uncovering the molecular underpinnings of organ morphogenesis and organoid technology, translation of regenerative medicine to the clinic has confronted with hurdles. These bottlenecks are in part due to the lack of understanding as to how niche cells coordinate organ repair. Specifically, contribution of vascular niche cells that supply regenerative signals has not been realized. This R35 application builds upon the novel proposition that poor healing after organ damage is due to the dysfunction and loss of the tissue-specific ECs. This programmatic proposal examines the hypothesis that reconstitution of stem cells in injured organs is dependent on the pro-regenerative angiocrine signals supplied by tissue-specific vascular niche ECs. We have shown that organotypic ECs by deploying defined angiocrine factors support lung, cardiac, hepatic and hematopoietic regeneration. Thus, ECs perform actively as dynamic, tissue-specified niche cells critical for tissue homeostasis and repair. To test this and to set up the stage for therapies, we have engineered adaptable mouse, nonhuman primate and human ECs by transducing the transduction factor (TF) ETV2 into adult mature ECs (R-VECs) and differentiating human induced pluripotent stem cells (iPSCs) into generic fetal-like ECs (iVECs) that could inform on the pathways that induce organotypic TFs. These adaptive iVECs and R-VECs will be cocultured with heart, lung, and blood organoids in vitro or infused in vivo in mice undergoing organ repair to identify the induction of organotypic TFs in these cells. The educated iVECs and R-VECs will be recovered and subjected to RNA profiling and de novo motif discovery to identify induced tissue-specific TF(s). The identified TFs will be overexpressed or knocked down in ECs, to validate their function in sustaining organotypic and angiocrine profile for organ repair. We anticipate that transplantation of organotypic ECs will promote long-lasting tissue repair without provoking tumorigenesis or fibrosis. We have initiated FDA-approved human clinical trials to examine the safety and efficacy of allogeneic generic EC infusion for hematopoietic recovery. As a follow up, we intend to assess the contribution of R-VECs or iVECs-derived from nonhuman primates to regeneration in the pigtail macaque monkeys with the intention of translating the potential of organotypic ECs to clinic. The expected outcomes of the proposed research are identification of molecular signals and transcriptional determinants of tissue-specific vascular and angiocrine heterogeneity. Goals of this proposal fit with the mission of NHLBI R35 award to develop innovative regenerative discovery pipeline to promote safe and efficacious treatments for cardiac, pulmonary and blood maladies.

项目摘要